IRAK-4 and MyD88 deficiencies impair IgM responses against T-independent bacterial antigens

• Published in: Blood Vol. 124; no. 24; pp. 3561 - 3571
• Main Authors: Maglione, Paul J., Simchoni, Noa, Black, Samuel, Radigan, Lin, Overbey, Jessica R., Bagiella, Emilia, Bussel, James B., Bossuyt, Xavier, Casanova, Jean-Laurent, Meyts, Isabelle, Cerutti, Andrea, Picard, Capucine, Cunningham-Rundles, Charlotte
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.12.2014; American Society of Hematology
• Subjects: Adolescent; Adult; Animals; Antibodies, Bacterial - genetics; Antibodies, Bacterial - immunology; Antigens, Bacterial - immunology; B-Lymphocytes - immunology; B-Lymphocytes - pathology; Bacterial Infections - genetics; Bacterial Infections - immunology; Bacterial Infections - pathology; Cells, Cultured; Child; Child, Preschool; Female; Humans; Immunobiology; Immunoglobulin G - immunology; Immunoglobulin M - genetics; Immunoglobulin M - immunology; Immunologic Deficiency Syndromes - genetics; Immunologic Deficiency Syndromes - immunology; Immunologic Deficiency Syndromes - pathology; Infant; Interleukin-1 Receptor-Associated Kinases - genetics; Interleukin-1 Receptor-Associated Kinases - immunology; Male; Middle Aged; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - immunology; Polysaccharides, Bacterial - immunology; Primary Immunodeficiency Diseases; Toll-Like Receptor 7 - genetics; Toll-Like Receptor 7 - immunology; Toll-Like Receptor 9 - genetics; Toll-Like Receptor 9 - immunology
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2014-07-587824

IRAK-4 and MyD88 deficiencies impair interleukin 1 receptor and Toll-like receptor (TLR) signaling and lead to heightened susceptibility to invasive bacterial infections. Individuals with these primary immunodeficiencies have fewer immunoglobulin M (IgM)+IgD+CD27+ B cells, a population that resembles murine splenic marginal zone B cells that mount T-independent antibody responses against bacterial antigens. However, the significance of this B-cell subset in humans is poorly understood. Using both a 610 carbohydrate array and enzyme-linked immunosorbent assay, we found that patients with IRAK-4 and MyD88 deficiencies have reduced serum IgM, but not IgG antibody, recognizing T-independent bacterial antigens. Moreover, the quantity of specific IgM correlated with IgM+IgD+CD27+ B-cell frequencies. As with mouse marginal zone B cells, human IgM+CD27+ B cells activated by TLR7 or TLR9 agonists produced phosphorylcholine-specific IgM. Further linking splenic IgM+IgD+CD27+ B cells with production of T-independent IgM, serum from splenectomized subjects, who also have few IgM+IgD+CD27+ B cells, had reduced antibacterial IgM. IRAK-4 and MyD88 deficiencies impaired TLR-induced proliferation of this B-cell subset, suggesting a means by which loss of this activation pathway leads to reduced cell numbers. Thus, by bolstering the IgM+IgD+CD27+ B-cell subset, IRAK-4 and MyD88 promote optimal T-independent IgM antibody responses against bacteria in humans. •Human IRAK-4 and MyD88 deficiencies impair T-independent IgM production, including IgM recognizing bacterial antigens.•T-independent IgM impairment by IRAK-4 and MyD88 deficiencies is linked to inadequacy of the IgM+IgD+CD27+ B-cell subset.